LV11319B - Hydroxamic acid derivatives - Google Patents

Hydroxamic acid derivatives Download PDF

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Publication number
LV11319B
LV11319B LVP-95-103A LV950103A LV11319B LV 11319 B LV11319 B LV 11319B LV 950103 A LV950103 A LV 950103A LV 11319 B LV11319 B LV 11319B
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Prior art keywords
lower alkyl
ethyl
dioxo
trimethyl
imidazolidinyl
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LVP-95-103A
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Latvian (lv)
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LV11319A (en
Inventor
Michael John Broadhurst
Paul Anthony Brown
William Henry Johnson
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Hoffmann La Roche
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Priority claimed from GB9408183A external-priority patent/GB9408183D0/en
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of LV11319A publication Critical patent/LV11319A/en
Publication of LV11319B publication Critical patent/LV11319B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/44—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides hydroxamic acid derivatives of the general formula <CHEM> wherein R<1> represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R<2> represents a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring which is attached via the N atom and which, when it is monocyclic, optionally contains NR<4>, O, S, SO or SO2 as a ring member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino,carboxy, lower alkoxycarbonyl, hydroxy-methyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyimino; R<3> represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO2 as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or oxo and/or on any additional N atom(s) by lower alkyl or aryl; R<4> represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; m stands for 1 or 2 and n stands for 1-4, and pharmaceutically acceptable salts thereof, which are collagenase inhibitors useful in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis. They can be manufactured either by hydroxamidating a corresponding novel carboxylic acid or by deprotecting a corresponding novel benzyloxycarbamoyl compound.

Description

LV 11319
The present invention is concemed with hydroxamic acid derivatives. 5 The hydroxamic add derivatives provided by the present invention are compounds of the general formula
R3 ω 10 wherein R1 represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R2 represents a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring which is attached via the N atom and which, when it is monocyclic, optionally contains NR4, 0, S, SO or SO2 as a ring 15 member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, 0x0, ketalized 0x0, amino, mono(lower alkyl)amino, di(lower alkyl) amino, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or 20 hydroxyimino; R3 represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO2 as an additional ring member, (c) is substituted by 0x0 on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-25 fused or optionally substituted on one or more other C atoms by lower alkyl or 0x0 and/or on any additional N atom(s) by lower alkyl or aryl; R4 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; m stands for 1 or 2; and
Lo/So 13.2.95 -2- n stands for 1-4; and pharmaceutically acceptable salts thereof.
The compounds of formula I possess valuable pharmacological properties. In particular, they are collagenase inhibitors and can be used in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis.
Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts per se and for use as therapeutically active substances; a process for the manufacture of said compounds and salts; intermediates useful in said process; medicaments containing said compounds and salts and the manufacture of these medicaments; and the use of said compounds and salts in the control or prevention of illnesses or in the improvement of health, especially in the control or prevention of degenerative joint diseases or in the treatment of invasive tumours or atherosclerosis, or for the manufacture of a medicament for the control or prevention of degenerative joint diseases or for the treatment of invasive tumours, atherosclerosis or multiple sclerosis.
As used in this Specification, the term &quot;lower alkyl&quot;, alone or in combination, means a straight-chain or branched-chain alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl and the like. The term ’lower alkoxy&quot;, alone or in combination, means a straight-chain or branched-chain alkoxy group containing a maximum of six carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert.butoxy and the like. The term &quot;aryr means phenyl which is optionally substituted by, for example, lower alkyl, lower alkoxy and/or halogen, i.e. fluorine, chlorine, bromine or iodine, such as p-tolyl, p-methoxyphenyl, p-chloro-phenyl and the like. The term &quot;aralkyl&quot; means a lower alkyl group as hereinbefore defined in which one or more hydrogen atoms is/are replaced by an aryl group as hereinbefore defined, such as benzyl and the like. A ketalized oxo group can be, for example, ethylenedioxy. -3- LV 11319 A protecting group denoted by R4 can be any conventional protecting group, e.g. as known in peptide chemistry such as benzyloxycarbonyl, tert.butoxy carbonyl, acetyl and the like. 5 Examples of monocyclic N-heterocyclic rings denoted by R2 are 1- pyrrolidinyl, piperidino, l-piperazinyl, 4-aryl-l-piperazinyl, hexahydro-l-pyridazinyl, morpholino, tetrahydro-l,4-thiazin-4-yl, tetrahydro-l,4-thiazin-4-yl l-oxide, tetrahydro-l,4-thiazin-4-yl l,l-dioxide, thiazolidin-3-yl, hexahydroazepino and octahydroazocino which can be substituted in the 10 manner given earlier; for example 2-(methylcarbamoyl)-l-pyrrolidinyl, 2-(hydroxymethyl)- l-pyrrolidinyl, 4-hydroxypiperidino, 2-(methyl-carbamoyl)piperidino, 4-hydroxyiminopiperidino, 4-methoxypiperidino, 4-methyl-l-piperazinyl, 4-phenyl-l-piperazinyl, l,4-dioxa-8-azaspiro[4.5]decan-8-yl, hexahydro-3-(methylcarbamoyl)-2-pyridazmyl, hexahydro-l-(benzyloxy-15 carbonyl)-2-pyridazinyl, 5,5-dimethyl-4-methylcarbamoyl-thiazolidin-3-yl and 5,5-dimethyl-4-propylcarbamoyl-thiazolidin-3-yl.
Examples of bridged N-heterocyclic rings denoted by R2 are 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.1]heptane, 7-azabicydo[2.2.1]-20 heptane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[3.2.2]nonane and 3-azabicyclo [3.2.2]nonane.
Examples of N-heterocyclic rings denoted by R3 are rings of the formulae: 25
(b) (c) -4-
5 in which R5 and R6 each represent hydrogen or together represent an additional bond or the remainder of a fused benzene ring; R7 represents hydrogen, lower alkyl or aryl; and X represents -CO-, -CH2-, -CHGower alkyl&gt;-, -CGower alkyl)2-, -NH-,
10 -NGower alkyl)- or -0-; or, when R7 represents lower alkyl and X represents -NGower alkyl)-, the lower alkyl groups can be joined to form a 5-, 6- or 7-membered ring; R8 represents hydrogen, lower alkyl or aryl; R9 and R10 each represent hydrogen or lower alkyl; 15 Y represents -O-, -NH- or -NGower alkyl)-; and Z represents S, SO or SO2;
Examples of such rings are 2-oxo-l-pyrrolidinyl, 2,5-dioxo-l-pyrrolidino, phthalimido, l,2-dimethyl-3,5-dioxo-l,2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo-l-imidazolidinyl, 3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl, 2-methyl-3,5-20 dioxo-l,2,4-oxadiazol-4-yl, 3-methyl-2,4,5-trioxo-l-imidazolidinyl, 2,5-dioxo-3-phenyl-l-imidazolidinyl, 2,6-dioxopiperidino, 5,5-dimethyl-2,4-dioxo-3-oxazolidinyl and hexahydro-l,3-dioxopyrazolo[l,2-a][l,2,4]triazol-2-yl.
One group of preferred compounds of formula I comprises those in 25 which R2 represents l-pyrrolidinyl, piperidino, 4-aryl-l-piperazino, morpholino, tetrahydro-l,4-thiazin-4-yl, tetrahydro-l,4-thazin-4-yl 1,1-dioxide, thiazolidin-3-yl, hexahydroazepino or octahydroazocino optionally -5- LV 11319 substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, ketalized oxo or mono(lower alkyl)-carbamoyl, espedally piperidino which is optionally substituted by hydroxy, particularly 4-hydroxypiperidino, or 3-azabicyclo[3.2.2]nonane. Also preferred are compounds of formula I in which R3 represents a group of formula (b), (c), especially one in which R7 represents lower alkyl and X represents -C(lower alkyl)2-, particularly 3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl, or (h). Preferably, m and n both stand for 1.
The most preferred compounds of formula I are: l-[3-Cyclopropyl-2(RHl(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo- l-imidazolidmyl)ethyl]propionyl]piperidine, l-[3-cyclopropyl-2-(R)-[l (R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo- l-imidazolidinyl)ethyl]propionyl]-4-piperidinol, 3-[3-cyclopropyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane, l-[3-cyclobutyl-2(R)-[l (R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo- l-imidazolidinyl)ethyl]propionyl]piperidine, l-[3-cyclobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-4-piperidinol, 3-[3-cyclobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane, l-[3-cyclopentyl-2[(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl] propionyl]-4-piperidinol, 3- [3-cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamyl)-2-[3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane and l-[3-cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]piperidine.
Other preferred compounds of formula I hereinbefore are: l-[3-cyclohexyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]piperidine, 4- [3-cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]tetrahydro-l,4-thiazine, -6- 4-[3-cydopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2f5-dioxo-l-imidazolidinyl)ethyl]propionyl]tetrahydro-l,4-thiazine S,S-dioxide, 4-[3-cyclobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]tetrahydro-l,4-thiazine, 4-[3-cydohexyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4&gt;4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]tetrahydro-l,4-thiazine&gt; 3- [3-cydopentyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo- 1-imidaz olidinyl)ethyl]propionyl]-5,5-dimethyl-N-propyl-4(R)-thiazolidinecarboxamide, 4- [3-cydopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4»4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]morpholine, 3- [3-cydopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl )-2-(3,4,4-trimethyl- 2.5- dioxo-l-iimdazoli(iinyl)ethyl]propionyl]-N,5,5-trimethyl-4(R)-thiazolidinecarboxamide, 4- [3-cydobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-4-phenylpiperazine, 4-[3-cydobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]morpholine, l-[3-cydobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4.4-trimethyl- 2.5- dioxo-l-iinidazolidinyl)ethyl]propionyl]pyrrolidine, 8-[3-cydobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-l,4-dioxa-8-azaspiro[4,5]decane, l-[3-cydobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-4-methoxypiperidine, l-[3-cydobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]octahydroazocine, l-[3-cydobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3-oxazolidinyl)ethyl]propionyl]piperidine, l-[3-cydobutyl-2(R)-[lCR or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]hexahydroazepine, l-[3-cydobutyl-2(RH2-(hexahydro-l&gt;3-dioxopyrazolo[l,2-a][l,2,4]triazol-2-yl)-l(R or S)-(hydroxycarbamoyl)ethyl]propionyl]piperidine and l-[3-cydobutyl-2(R)-[l(R or SHhydroxycarbamoyD-2-phthaKmido-ethyl]propionyl]piperidine.
The compounds of formula I form pharmaceutically acceptable salts with bases such as alkali mētai hydroxides (e.g. sodium hydroxide and -7- LV 11319 potassium hydroxide), alkaline earth mētai hydroxides (e.g. calcium hydroxide and magnesinm hydroxide), ammonium hydroxide and the like. The compounds of formula I which are basie form pharmaceutically acceptable salts with acids. As such salts there come into consideration not 5 only salts with inorganic adds such as hydrohahc acids (e.g. hydrochloric add and hydrobromic add), sulphuric add, nitric add, phosphoric add etc, but also salts with organic adds such as acetic add, tartaric add, sucdnic add, fumaric add, maleic add, malic add, salicylic add, dtric add, methanesulphonic add, p-toluenesulphonic add etc. 10
The compounds of formula I contain at least two asymmetric carbon atoms and can accordingly exist as optically active enantiomers, as diastereoisomers or as racemates. The present invention is intended to embrace ali of these forms. 15
According to the process provided by the present invention, the compounds of formula I and their pharmaceutically acceptable salts are manufactured by 20 (a) reacting an add of the general formula R1
wherein R1, R2, R3, m and n have the significance given earlier, 25 with a compound of the general formula h2n-oz m wherein Z represents hydrogen, tri(lower alkyl)silyl or diphenylQower 30 alkyl)silyl, - 8 - and, where required, cleaving off any diphenyl(lower alkyl)silyl group present in the reaction product, or (b) catalytically hydrogenating a compound of the general formula R1
(IV) wherein R1, R2, R3, m and n have the significance given earlier and
Bz represents benzyl, and, if desired, converting a compound of formula I obtained into a pharmaceutically acceptable salt.
The reaction of an acid of formula Π with a compound of formula III in accordance with embodiment (a) of the process can be carried out in a known manner. For example, an acid of formula II can be reacted with a compound of formula ΙΠ in an inert organic solvent such as dichloro-methane, dimethylformamide or the like using l-hydroxybenzotriazole in the presence of a condensation aģent such as l-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride at about 0°C to about room temperature. Altematively, an acid of formula Π can be converted into the corresponding add chloride (e.g. using oxalyl chloride) and the acid chloride can then be reacted with a compound of formula III. Preferred compounds of formula III are those in which Z represents tert.butyldimethylsilyl or tert.butyl-diphenylsilyl. When a compound of formula III in which Z represents triGower alkyl)silyl is used, this group is cleaved off during the reaction and working-up, and a compound of formula I is obtained directly. On the other hand, when a compound of formula ΙΠ in which Z represents diphenyl-(lower alkyl)silyl is used, this group remains in the reaction product and -9- LV 11319 must subsequently be cleaved off in a known manner, for example by means of fluoride ions.
The catalytic hydrogenation of a compound of formula IV in accordance with embodiment (b) of the process can be carried out in a manner known per se; for example in an inert organic solvent using hydrogen in the presence of a noble mētai catalyst. Suitable inert organic solvents are, for example, lower alkanols such as methanol, ethanol, etc. With respect to the catalyst, this can be, for example, a platinum, palladium or rhodium catalyst which can be supported on a suitable carrier material. Palladium-on-charcoal is the preferred catalyst. The temperature and pressure are not critical, although for convenience the catalytic hydrogenation is preferably carried out at room temperature and under atmospheric pressure.
Compounds of formula I can be converted into pharmaceutically acceptable salts by treatment with bases and basie compounds of formula I can be converted into pharmaceutically acceptable salts by treatment with acids. Such treatments can be carried out in a conventional manner.
The acids of formula II which are used as starting materiāls in embodiment (a) of the process are novel and form a further object of the present invention.
The acids of formula II can be prepared, for example, as illustrated in the following Reaction Scheme in which R1, R2, R3, m and n have the significance given earlier, Bz represents benzyl and tBu represents tert-butyl: -10- -10- R1
Reaction Scheme R1 R1 NaNO, (CH2)m I -(CH2)m - Λ ' COOH HO/COOH (V) (VI)
BzBr (CH2)m HO^ COOBz (VII)
Alkylarion tBu- R3- tBu R3-
Debenzyladon O o (CH2)n- (XI)
t R1 I (CH2)m COOH COOH
R1
Deprotection
R2 (II) -11- LV 11319
Having regard to the foregoing Reaction Scheme, the individual steps thereof can be carried out according to methods known per se. Thus, in the first step, an amino acid of formula V, which can be obtained according to the procedure described by Chenault H.K, Dahmer J. and Whitesides G.M., J.Am.Chem.Soc. 1989,111, 6354-6364, is converted by treatment with sodium nitrite in the presence of concentrated sulphuric acid into a hydroxy acid of formula VI which is subsequently reacted with benzyl bromide in the presence of an organic base, e.g. a trialkylamine such as triethylamine, into a corresponding benzyl ester of formula VII. The latter is then activated, e.g. by reaction with trifluoromethanesulphonic anhydride, and treated with benzyl tert-butyl malonate in the presence of a strong base, e.g. an alkali mētai hydride such as sodium hydride, to give a compound of formula VIII. Treatment of the latter with a strong base, e.g. an alkali mētai hydride such as sodium hydride, and reaction with a compound of formula IX yields a dibenzyl tert-butyl butanetricarboxylate of formula X which is then debenzylated by catalytic hydrogenation, e.g. in the presence of a palladium catalyst such as palladium-on-charcoal, to give a tert-butyl dihydrogen butanetricarboxylate of formula XI. Decarboxylation of this compound, e.g. by heating in toluene with triethylamine, which may be carried out in situ, yields a tert-butyl hydrogen succinate of formula XII which is condensed with a cyclic amine of formula XIII, e.g. according to the acid chloride method or using l-hydroxybentriazole in the presence of a condensation aģent such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, to give a compound of formula XIV which is deprotected (e.g. by treatment with trifluoroacetic acid) to give an acid of formula Π.
The compounds of formula IV which are used as starting materiāls in embodiment (b) of the process are novel and form a further object of the present invention.
The compounds of formula IV can be prepared, for example, by reacting an acid of formula II with 0-benzylhydroxylamine. This reaction can be carried out in a known manner, for example in an inert organic solvent such as dichloromethane or dimethylformamide using 1-hydroxybenzotriazole in the presence of a condensation aģent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. -12-
The remaining compounds which are used as intermediates or reactants in the manufacture of the compounds of formula I are known compounds or analogues of known compounds which can be prepared in a similar manner to the known compounds. 5
As mentioned earlier, the compounds of formula I and their pharmaceutically acceptable salts are collagenase inhibitors. The in vitro collagenase inhibiting activity of the present compounds and salts can be demonstrated using collagenase obtained from a culture of human synovial 10 fibroblasts according to the method of Dayer J-M et al., Proc. Nati. Acad. Sd. USA (1976), 22 945, following activation of the pro-collagenase in the conditioned medium by treatment with trypsin. Collagenase activity was measured using 14C-acetylated collagen type I from rat tail tendons as the substrate and employing the microtitre plate assay method of Johnson-Wint, 15 B, Anal. Biochem. (1980), 104,175. The IC50 is that concentration of a compound or salt of the present invention in the enzyme digestion which reduces substrate deavage and solubihzation to 50% of that achieved by the enzyme alone. 20 The results obtained in the foregoing tēst with representative compounds and salts of this invention are compiled in Table I hereinafter:
Table I
Product of Example No. IC50 (nM) 2 18.0 4 7.0 5 2.5 7 6.5 9 8.5 16 4.1 17 2.35 23 34.0
The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharma-ceutical preparations. The pharmaceutical preparations can be admin-istered orally, e.g. in the form of tablets, coated tablets, dragēes, hard and -13- LV 11319 soft gelatine capsules, Solutions, emulsions or suspensions. However, they can also be administered rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection Solutions.
For the manufacture of pharmaceutical preparations the compounds of formula I and their pharmaceutically acceptable salts can be formulated with therapeutically inert, inorganic or organic carriers. Lactose, com starch or derivatives thereof, talc, stearic add or its salts can be used, for example, as such carriers for tablets, coated tablets, dragēes and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active ingredient no carriers are, however, generally required in the case of soft gelatine capsules. Suitable carriers for the manufacture of Solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose and the like. Suitable carriers for the manufacture of injection Solutions are, for example, water, alcohols, polyols, glycerine, vegetable oils and the like. Natūrai and hardened oils, waxes, fats, semi-liquid polyols and the like are suitable carriers for the manufacture of suppositories.
The pharmaceutical preparations can also contain preservatives, stabilizers, wetting aģents, emulsifiers, sweeteners, colorants, flavorants, salts for adjustment of the osmotic pressure buffers coating aģents or antioxidants.
Medicaments containing a compound of formula I or a pharma-ceutically acceptable salt thereof and a therapeutically acceptable carrier as well as a process for the manufacture of such medicaments are also objects of the present invention. This process comprises mixing a compound of formula I or a pharmaceutically acceptable salt thereof with a therapeuti-cally inert carrier material and bringing the mixture into a galenical administration form.
As mentioned earlier, the compounds of formula I and their pharma-ceutically acceptable salts can be used in the control or prevention of illnesses, espedally in the control or prevention of degenerative joint diseases or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis. The dosage can vary within wide limits and will, of course, be -14- adjusted to the individual requirements in each particular case. In general, in the case of administration to adults, a daily dosage of from about 5 mg to about 30 mg, preferably from about 10 mg to about 15 mg, should be appropriate, although the upper limit may be exceeded when this is found to be expedient. The daily dosage can be administered as a single dosage or in divided dosages.
The following Examples illustrate the present invention in more detail. In these Examples ali temperatures are given in degrees Celsius.
Example 1 A solution of0.575 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]piperidine (diastereoisomer 1) in 10 ml of ethanol was hydrogenated in the presence of 0.4 g of 5% palladium-on-charcoal catalyst for 6 hours. The catalyst was removed by filtration and the solution was evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/ methanol (96:4) for the elution to give 0.37 g of l-[3-cyclopropyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-propionyl]piperidine (diastereoisomer 1) in the form of a white foam. nmr (MeOD): 3.78-3.64 (m, 3H); 3.62 (dd, 1H, J = 15,8); 3.49-3.41 (m, 1H); 3.39 (dd, 1H, J = 15,5); 3.33-3.27 (m, 1H); 2.95-2.87 (m, 1H); 2.83 (s, 3H); 1.74-1.46 (m, 7H); 1.33 (s, 3H); 1.31 (s, 3H); 1.20-1.13 (m, 1H); 0.61-0.50 (m, 1H); 0.44-0.33 (m, 2H); 0.06- -0.05 (m, 2H); MS: 409 (M+H)+.
The starting material was prepared as follows: (i) A solution of 4.9 g of 2(R)-amino-3-cyclopropylpropionic add (prepared in a manner analogous to that described by Chenault H.K., Dahmer J. and Whitesides G.M. in J. Am. Chem. Soc. 1989,111, 6354-6364) in 50 ml of water containing 4.05 ml of concentrated sulphuric acid was warmed to 45°. A solution of 10.5 g of sodium nitrite in 20 ml of water was added dropwise over 30 minūtes. The solution was stirred at 45° for 4 hours and then cooled to room temperature. The solution was extracted with three 50 ml portions of ethyl acetate. The combined extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was evaporated to leave 3.95 g -15- LV 11319 of a yellow oil containing 3-cydopropyl-2(R)-hydroxypropionic acid which was used in the next step without further purification.
Rf [dichloromethane/methanol (9:1)] = 0.65. 5 (ii) A solution of 3.95 g of the product from (i) in 50 ml of ethyl acetate was treated with 5.32 ml of triethylamine and 3.8 ml of benzyl bromide. The mixture was stirred and heated under reflux for 3 hours, then allowed to cool to room temperature overnight. The suspension was washed with 2M hydrochloric acid, water and saturated sodium chloride solution. After 10 drying over anhydrous magnesium sulphate the solvent was evaporated.
The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) for the elution to give 3.36 g of benzyl 3-cyclopropyl-2(R)-hydroxypropionate in the form of a yellow oil. nmr (CDC13): 7.39-7.28 (m; 5H); 5.19 (d, 1H, J = 14); 5.15 (d, 1H, J= 14); 4.31-15 4.24 (m, 1H); 2.81 (br. d, IH); 1.69-1.54 (m, 2H); 0.87-0.74 (m, 1H); 0.45-0.34 (m, 2H); 0.08- -0.07 (m, 2H). (iii) A solution of 3.36 g of the product from (ii) and 1.49 ml of pyridine in 10 ml of dichloromethane was added dropwise to a solution of 3.07 ml of 20 triiluoromethanesulphonic anhydride in 15 ml of dichloromethane at 0° over 30 minūtes with stirring. The mixture was stirred at 0° for 2 hours and then washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the solvent was evaporated to give 5.37 g of benzyl 3-cyclopropyl-2(R&gt;trifluoromethylsulphonyloxypropionate in the 25 form of an orange oil which was used in the next step without further purification.
Rf [hexane/ethyl acetate (4:1)] = 0.5. (iv) A solution of 3.8 g of benzyl tert-butyl malonate in 50 ml of 1,2- 30 dimethoxyethane was treated with 0.504 g of an 80% dispersion of sodium hydride in mineral oil. The mixture was stirred at room temperature for 30 minūtes and then cooled to 0°. A solution of 5.37 g of the product from (iii) in 20 ml of dichloromethane was added dropwise at 0°. The mixture was stirred at 0° for 2 hours and then left to warm to room temperature 35 overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the solvent was evaporated to give 6.54 g of 2,3-dibenzyl 3-tert-butyl l-cyclopropyl- -16- 2(R),3(R,S),3-propanetricarboxylate as a 1:1 mixture of diastereoisomers in the form of an orange oil. nmr (CDC13): 7.46-7.36 (m, 20H); 5.19-5.07 (m, 8.H); 3.89 (d, 1H, J =10); 3.85 (d, 1H, J= 10) 3.37-3.26 (m, 2H); 1.68-1.52 (m, 2H); 1.52-1.38 (m, 2H); 1.41 (s, 9H); 1.39 (s, 9H); 0.79-0.63 (m, 2H); 0.49-0.38 (m, 4H); 0.12-0.07 (m, 4H). (v) A solution of 6.4 g of the product from (iv) in 30 ml of l,2-dimethoxy-ethane was treated with 0.446 g of an 80% dispersion of sodium hydride in mineral oil. The mixture was stirred at room temperature for 30 minūtes. A solution of 3.84 g of l-(bromomethyl)-3,4,4-tiimethyl-2,5-imidazolinedione in 20 ml of l,2-dimethoxyethane was added dropwise over 15 minūtes. The mixture was stirred at room temperature for 36 hours, the solvent was evaporated and the residue was dissolved in ethyl acetate and washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the solvent was evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (7:3) and subsequently hexane/ethyl acetate (6:4) for the elution to give 6.4 g of 2,3-dibenzyl 3-tert-butyl l-cyclopropyl-4-(3,4,4-trimethyl-2, 5-dioxo-l-imidazoli-dinyl)-2(R),3(R,S),3-butanetricarboxylate as a 1:1 mixture of diastereoisomers in the form of a dear oil. nmr (CDCI3): 7.47-7.28 (m, 20H); 5.31-5.03 (m, 8H); 4.32-4.18 (m, 4H); 3.19-3.15 (m, 1H); 3.16-3.12 (m, 1H); 2.86 (s, 6H); 2.00-1.90 (m, 1H); 1.89-1.79 (m, 1H); 1.64-1.49 (m, 1H); 1.48-1.38 (m, 1H); 1.37 (s, 12H); 1.36 (s, 9H); 1.32 (s, 9H); 0.9-0.8 (m, 2H); 0.41-0.3 (m, 4H); 0.15-0.05 (m, 2H); 0.04- -0.04 (m, 2H). (vi) A solution of 3.0 g of the product from (v) in 30 ml of 2-propanol was hydrogenated in the presence of 0.3 g of 5% palladium on charcoal catalyst for 2 hours. The catalyst was removed by filtration and the solution was evaporated. The residue was re-evaporated from 20 ml toluene and then dissolved in 50 ml of toluene. The solution was treated with 0.693 ml of triethylamine and the mixture was heated under reflux for 2 hours. The solution was cooled to room temperature and washed with 2M hydrochoric add, water and saturated sodium chloride solution. After drying over anhydrous magnesium suphate the solvent was evaporated to give 1.85 g of 4-tert-butyl hydrogen 2(R)-(cydopropylmethyl)-3(R or S)-[(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)methyl]sucdnate as an approximately 6:1 mixture of diastereoisomers in the form of a yellow oil. MS: 383 (M+H)+; -17- LV 11319
Rf [dichloromethane/methanol (9:1)] = 0.41. (vii) A solution of 1.0 g of the product from (vi) in 10 ml of dichloromethane was cooled to 0° and treated in succession with 0.665 ml of N-ethylmor-pholine, 0.481 g of l-hydroxybenzotriazole and 0.602 g of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred at 0° for 30 minūtes and then treated with 0.517 ml of piperidine. The solution was left to warm to room temperature and was stirred ovemight. The solution was washed with 5% aqueous sodium hydrogen carbonate solution, 2M hydrochloric acid and saturated sodium chloride solution.
After drying over anhydrous magnesium sulphate the solvent was evap-orated to give 1.01 g of of 1-[2(R)-[1(R or S)-(tert-butoxycarbonyD-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]piperidine as an approximately 6:1 mixture of diastereoisomers in the form of a yellow gum. MS: 450 (M+H)+;
Rf [dichloromethane/methanol (95:5)] = 0.51. (viii) A solution of 1.0 g of the product from (vii) in 2 ml of trifluoroacetic acid was stirred at room temperature for 2.5 hours. The solvent was evaporated and the residue was re-evaporated from toluene. The residue was dissolved in diethyl ether and the solution was extracted with two portions of 5% aqueous sodium hydrogen carbonate solution. The combined extracts were acidified to pH 2 with concentrated hydrochloric acid and the product was extracted with two portions of dichloromethane. The combined organic extracts were washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The solvent was evaporated to give 0.634 g of a white foam containing 1-[2(R)-[1(R or S)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopropyl-propionyl]piperidine as a 6:1 mixture of diastereoisomers which was used in the next step without further purification.
Rf [dichloromethane/methanol (9:1)1 = 0.31. (ix) A solution of 0.634 g of the product from (viii) in 10 ml of dichloromethane was cooled at 0°. The solution was treated in succession with 0.41 ml of N-ethylmorpholine, 0.296 g of l-hydroxybenzotriazole and 0.371 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred at 0° for 30 minūtes. A solution of 0.238 g of 0-benzylhydroxyl- -18- amine in 2 ml of dichloromethane was added. The mixture was lefl to warm to room temperature and was stirred overaight. The solution was washed with two portions of 5% aqueous sodium hydrogen carbonate solution and subsequently with 2M hydrochloric acid, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the solvent was removed by evaporation. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (98:2) for the elution to give 0.592 g of 1-[2(RM1(R or SMbenzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]piperidine (diastereoisomer 1) as a white foam. nmr (MeOD): 7.45-7.31 (m, 5H); 4.87 (d, 1H, J = 13); 4.79 (d, 1H, J = 13); 3.78-3.65 (m, 3H); 3.63 (dd, 1H, J = 15,8); 3.53-3.45 (m, 1H); 3.44 (dd, 1H, J = 15,5); 3.34-3.27 (m, 1H); 2.87 (s, 3H); 2.84-2.78 (m, 1H); 1.78-1.49 (m, 7H); 1.49-1.40 (m, 1H); 1.36 (s, 3H); 1.32, (s, 3H); 1.12-1.04 (m, IH); 0.61-0.50 (m, 1H); 0.48-0.37(m, 2H); 0.07- -0.06 (m, 2H). MS: 499 (M+H)+.
Example 2
In a manner analogous to that described in the first paragraph of Example 1, from 0.391 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]-4-piperidinol (diastereoisomer 1), prepared in a manner analagous to that described in Example 1 (i)-(ix), there was obtained 0.33 g of l-[3-cyclopropyl-2-(RH1 (R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imida-zolidinyl)ethyl]propionyl]-4-piperidinol (diastereoisomer 1) in the form of a white foam. nmr (MeOD): 4.22-4.02 (m, 2H); 3.90-3.81 (m, 1H); 3.69-3.56 (m, 1H); 3.49-3.38(m, 2H); 3.37-3.18 (m, 2H); 3.11-3.01 (m, 1H); 2.97-2.86 (m, 1H); 2.83 (d, 3H, J = 5); 2.01-1.78 (m, 2H); 1.68-1.36 (m, 3H); 1.33 (s, 3H); 1.31 (d, 3H, J = 5); 1.24-1.13 (m, 1H); 0.62-0.50 (m, 1H); 0.49-0.33 (m, 2H); 0.09- -0.05 (m, 2H); MS: 425 (M+H)+
Example 3
In a manner analogous to that described in the first paragraph of Example 1, from 0.822 g of 3-[2(RMl(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopropyl]-3-azabicyclo- -19- LV 11319 [3.2.2]nonane (diastereoisomer 1), prepared in a manner analagous to that described in Example 1 (i)-(ix), there was obtained 0.496 g of 3-[3-cyclopropyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imida-zolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane (diastereoisomer 1) in 5 the form of a white foam. nmr (MeOD): 4.0-3.1(m, 5H); 3.48-3.31 (m, 2H); 2.96-2.86 (m, 1H); 2.82 (s, 3H); 2.14-2.03 (m,2H); 1.80-1.68 (m, 4H); 1.68-1.53(m, 5H); 1.32 (s, 3H); 1.31 (s, 3H); 1.21-1.12 (m, 1H), 0.64-0.52(m, 1H); 0.45-0.33 (m, 2H); 0.08- -0.05 (m, 2H); MS: 449 (M+H)+. 10
Examnle 4
In a manner analogous to that described in the first paragraph of Example 1, from 0.6 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-15 trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]piperidine (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), there was obtained 0.5 g of l-[3-cyclobutyl-2(R)-[l (R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2, 5-dioxo-l-imidazolidinyl)ethyl]-propionyl]piperidine (diastereoisomer 1) in the form of a white foam. 20 nmr (MeOD): 3.67 (dd, 1H, J = 15,10); 3.64-3.46 (m, 4H); 3.34 (dd, 1H, J = 15,8); 3.12 (td, 1H, J = 13,3); 2.92-2.84 (m, 1H); 2.82 (s, 3H); 2.22-2.09 (m, 1H); 2.07-1.93 (m, 2H); 1.90-1.42 (m, 12H); 1.33 (s, 3H); 1.32 (s, 3H); MS: 423 (M+H)+. 25 Example 5
In a manner analogous to that described in the first paragraph of Example 1, from 0.4 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-4-'30 piperidinol (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), there was obtained 0.294 g of l-[3-cydobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-piperidinol in the form of a white foam. nmr (MeOD): 4.15-4.05 (m, 1H); 4.04-3.90 (m, 1H); 3.90-3.80 (m, 1H); 3.72-3.57 35 (m, 1H); 3.45-3.30 (m,2H); 3.18-3.06 (m, 2H); 2.94-2.85 (m,lH); 2.84 (d, 3H, J = 5); 2.21-1.36 (m, 13H); 1.33 (d, 3H, J = 3); 1.31(d, 3H, J = 6); MS: 439 (M+H)+. -20-
Example 6
In a manner analogous to that described in the first paragraph of Ezample 1, from 0.642 g of 3-[2(R)-[l(R or SMbenzyloxycarbamoyl)-2-(3,4,4-5 trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclobutyl]-3-azabicyclo- [3.2.2]nonane (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), there was obtained 0.348 g of 3-[3-cyclobutyl-2(R&gt;[1(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imida-zolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane (diastereoisomer 1) in 10 the form of a white foam. nmr (MeOD): 3.92 3.83 (m, 2H); 3.76 (dd, 1H, J = 15,13); 3.67-3.57 (m, 2H); 3.34 (dd, 1H, J = 15,5); 3.28-3.21 (m, 1H); 2.96-2.87 (m, 1H); 2.83 (s, 3H); 2.23-2.13 (m,lH); 2.12-1.92 (m, 4H); 1.91-1.48 (m,14H); 1.35(s, 3H); 1.34 (s, 3H). MS: 463 (M+H)+. 15
Examole 7
In a manner analogous to that described in the first paragraph of Example 1, from 0.5 g of 1-[2(R)-[1(R or SMbenzyloxycarbamoyl)-2-(3,4,4-20 trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]-4-piperidinol (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), there was obtained 0.4 g of l-[3-cyclopentyl-2[(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-piperidinol (diastereoisomer 1) in the form 25 of a white foam. nmr (MeOD): 4.20-4.02 (m, 2H); 3.91-3.83 (m, 1H); 3.76-3.64 (m, lH);3.48-3.32 (m, 2H); 3.26-3.08 (m, 3H); 2.05-1.42 (m, 12H); 1.38-1.25 (m, 7H); 1.18-1.01 (m, 3H); MS: 453 (M+H)+. 30
Examnle 8
In a manner analogous to that described in the first paragraph of Example 1, from 0.57 g of 3-[2(R)-[l(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-35 trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopentyl]-3-azabicyclo-[3.2.2]nonane (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), there was obtained 0.48 g of 3-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamyl)-2-[3,4,4-trimethyl-2,5-dioxo-l- -21- LV 11319 imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane (diastereoisomer 1) in the form of a white foam. nmr (MeOD): 3.88-3.67 (m, 5H); 3.39-3.31 (m, 2H); 2.92-2.85 (m, 4H); 2.15-2.06 (m, 2H); 1.83 -1.45 (m, 16H); 1.36-1.28 (m, 7H; 1.16-1.02 (m, 2H). MS: 477 (M+H)+.
Example 9 A solution of 0.421 g of an approxiinately 6:1 mixture of diastereoisomer 1 and diastereoisomer 2 of 1-[2(R)-[1(R or S&gt;carboxy-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine, prepared in a manner analogous to that described in Example l(i)-(viii), in 10 ml of dichloromethane was cooled to 0°. The solution was treated with 0.211 g of l-hydroxybenzotriazole, 0.24 g of l-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride and 0.22 ml of N-methylmorpholine. The mixture was stirred at 0° for 15 minūtes. A solution of 0.295 g of 0-(tert-butyldimethylsilyl)hydroxylamine and 0.22 ml of N-methylmorpholine in 5 ml of dichloromethane was added. The mixture was left to warm to room temperature and was stirred ovemight. The solution was washed with two portions of 5% aqueous sodium hydrogen carbonate solution and subsequently with 2M hydrochloric acid and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the solvent was evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/ methanol (96:4) for the elution to give 0.123 g of l-[3-cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]piperidine (diastereoisomer 1) in the form of a white foam. nmr (MeOD): 3.74-3.66 (m, 3H); 3.53-3.45 (m, 2H); 3.34 (dd, J = 14,7,1H); 3.23 (dt, J = 4,14,1H); 2.90-2.84 (m, 4H); 1.80-1.45 (m, 14H); 1.38-1.23 (m, 7H); 1.15-1.01 (m, 2H); MS: 437 (M+H)+.
gxaņipļĢ 1Q
In a manner analogous to that described in the first paragraph of Example 1, starting from 0.328 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl&gt;2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclohexylpropionyl]-piperidine (diastereoisomer 1), prepared in a manner analogous to that -22- described in Example 1 (i)-(ix), there was obtained 0.269 g of l-[3-cyclohexyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazoli-dinyl)ethyl]propionyl]piperidine (diastereoisomer 1) in the form of a white foam. nmr (MeOD): 3.87-3.77 (m, 2H); 3.7 (dd, J = 14,9,1H); 3.64-3.56 (m, 2H); 3.38-3.28 (m, 2H); 2.9-2.83 (m, 4H); 1.84-1.45 (m, 12H); 1.35(s, 3H); 1.33 (s, 3H); 1.25-1.05 (m, 5H); 0.98-0.78 (m, 2H). MS: 451 (M+H)+.
Example 11
In a manner analogous to that described in Example 9, starting from 0.8 g of 1-[2(R)-[1(R or S&gt;carboxy-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazoli-dinyl)ethyl]-3-cyclopentylpropionyl]-tetrahydro-l,4-thiazine (diastereoisomer 1)(&gt; prepared in a manner analogous to Example 1 (i)-(viii), there was obtained 0.3 g of 4-[3-cyclopentyl-2(R)-[l-(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-tetrahydro-l,4-thiazine (diastereoisomer 1) in the form of a white foam. nmr (MeOD): 4.02-3.96 (m, 2H); 3.92-3.85 (m, 2H); 3.7 (dd, J = 13,9,1H); 3.37 (dd. J = 13,6,1H); 3.25-3.18 (m, 1H); 2.9-2.84 (m, 4H); 2.82-2.75 (m, 1H); 2.7-2.55 (m, 3H); 1.78-1.45 (m, 8H); 1.35 (s, 3H); 1.34 (s, 3H); 1.18-1.04 (m, 2H). MS: 455 (M+H)+.
Examnle 12
In a manner analogous to that described in Example 1, starting from 0.3 g of 4-[2(R)-[l(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]-tetrahydro-l,4-thiazine S,S-dioxide (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), there was obtained 0.2 g of 4-[3-cyclopentyl-2(R)-[1-(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-tetrahydro-l,4-thiazine S,S dioxide (diastereoisomer 1) in the form of a white solid. nmr (MeOD): 4.45-4.3 (m, 2H); 4.0-3.93 (m, 1H); 3.78-3.65 (m, 2H); 3.55-3.39 (m, 2H); 3.30-3.21 (m, 2H); 3.14-3.03 (m, 2H); 2.9-2.85 (m, 4H); 1.78-1.45 (m, 9H); 1.36 (s, 3H); 1.34 (s, 3H); 1.18-1.0 (m, 2H). MS: 487 (M+H)+. -23- LV 11319
Exanvple 13
In a manner analogous to that described in Example 9, starting from 0.8 g of 1-[2(R)-[1(R or S)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-tetrahydro-l,4-thiazine (diastereoisomer 1), prepared in a manner analogous to Example 1 (i)-(viii), there was obtained 0.24 g of 4-[3-cyclobutyl-2(R)-[l-(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-tetrahydro-l,4-thiazine (diastereoisomer 1) in the form of a white solid. nmr (MeOD): 3.98-3.75 (m, 4H); 3.64 (dd, J = 13,8,1H); 3.35 (dd, J = 15,6,1H); 3.07 (td, J = 10,4,1H); 2.9-2.83 (m, 1H); 2.82 (s, 3H); 2.78-2.72 (m, 1H); 2.66-2.52 (m, 3H); 2.18-2.08 (m, 1H); 2.05-1.93 (m, 2H); 1.85-1.45 (m, 6H); 1.13 (s, 3H); 1.11 (s, 3H). MS: 441 (M+H)+.
Example 14
In a manner analogous to that described in Example 9, starting from 1.22 g of 1-[2(R)-[1-(R or S&gt;carboxy-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclohexylpropionyl]-tetrahydro-l,4-thiazine (diastereoisomer 1), prepared in a manner analogous to Example 1 (i)-(viii), there was obtained 0.45 g of 4-[3-qydohexyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-tetrahydro-l,4-thiazine(diastereoisomer 1) in the form of a white solid. nmr (MeOD): 4.12-4.03 (m, 2H); 3.95-3.88 (m, 1H); 3.75-3.65 (m, 2H); 3.38 (dd, J = 14,6,1H); 2.88-2.82 (m, 4H); 2.78-2.72 (m, 1H); 2.68-2.55 (m, 3H); 1.82-1.53 (m, 7H); 1.35 (s, 3H); 1.34 (s, 3H); 1.26-0.8 (m, 8H); MS: 469 (M+H)+.
Example 15
In a manner analogous to that described in Example 9, from 1.164 g of a mixture of diastereoisomers of 3-[2(RMl(RS)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]-5,5-dimethyl-N-propyl-4(R)-thiazolidinecarboxamide, prepared in a manner analogous to that described in Example 1 (i)-(viii), there was obtained 0.329 g of 3-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazoli- -24- dinyl)ethyl]propionyl]-5,5-dimethyl-N-propyl-4(R)-thiazolidinecarboxamide (diastereoisomer 1) in the form of a white solid. nmr (MeOD): 5.09-4.72 (m, 2H); 4.51 and 4.46 (both s, total 1H); 3.84 and 3.64 (both dd, J = 14,8,1H); 3.40-3.05 (m, 4H); 2.90-2.73 (m, 4H); 1.94-1.25 (m, 23H); 1.23-1.01 (m. 2H); 0.99-0.85 (m, 3H); MS: 554 (M+H)+.
Example 16
In a manner analogous to that described in the first paragraph of Example 1, from 0.223 g of 4-[2(R)-[R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo- l-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]-morpholine (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (iMix), there was obtained 0.112 g of 4-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]morpholine (diastereoisomer 1) in the form of a white solid. nmr (MeOD): 3.83-3.56 (m, 9H); 3.41 (dd, J = 14,6,1H); 3.19 (dt, J = 4,11,1H); 2.91-2.81 (m, 4H); 1.77-1.42 (m, 8H); 1.38-1.23 (m, 7H); 1.19-0.99 (m, 2H); MS: 439 (M+H)+.
Examnle 17
In a manner analogous to that described in Example 9, from 1.289 g of a mixture of diastereoisomers of 3-[2(R)-[l(RS)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]-N,5,5-trimethyl-4(R)-thiazolidinecarboxamide (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (iMviii), there was obtained 0.629 g of 3-[3-cyclopentyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-N,5,5-trimethyl-4(R)-thiazolidine-carboxamide (diastereoisomer 1) in the form of a white solid. nmr (MeOD): 4.09-4.51 (m, 2H); 4.47 and 4.43 (both s, total 1H); 3.82 and 3.62 (both dd, J = 14,10, total 1H); 3.37 and 3.17 (both dd, J = 14,5, total 1H); 3.13-2.70 (m, 8H); 1.96-1.25 (m, 21H); 1.23-0.99 (m, 2H); MS: 526 (M+H)+. -25- LV 11319
Example 18
In a manner analogous to that described in the first paragraph of Example 1, from 0.289 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,.5-dioxo-l-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-4-phenylpiperazine (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), there was obtained 0.121 g of l-[3-cydobutyl-2(R)-[l(R or S)-[(hydroxycarbamoyl)methyl]-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-phenylpiperazine (diastereoisomer 1) in the form of a white solid. nmr (MeOD): 7.25 (m, 2H); 7.00 (m, 2H); 6.85 (m, 1H); 3.94-3.73 (m, 4H); 3.66 (dd, J = 14,7,1H); 3.43 (dd, J = 14,6,1H); 3.23-3.09 (m, 4H); 2.96-2.84 (m, 1H); 2.84 (s, 3H); 2.27-2.13 (m, 1H); 2.09-1.95 (m, 2H); 1.90-1.48 (m, 6H); 1.35 (s, 3H); 1.34 (s, 3H); MS:499 (M)+.
Examnle 19
In a manner analogous to that described in the first paragraph of Example 1, from 0.455 g of 4-[2(R)-[l(R or S)-benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cydobutylpropionyl]morpholine (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), there was obtained 0.194 g of 4-[3-cyclobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-propionyl]morpholine (diastereoisomer 1) in the form of a white solid. nmr (MeOD): 3.80-3.51 (m, 9H); 3.42 (dd, J = 14,6,1H); 3.14-3.06 (dt, J = 4,11,1H); 3.04-2.86 (m, 1H); 2.85 (s, 3H); 2.23-2.11 (m, 1H); 2.06-1.95 (m, 2H); 1.91-1.73 (m, 2H); 1.71-1.46 (m, 4H); 1.35 (s, 3H); 1.34 (s, 3H); MS:425 (M)+.
Example 20
In a manner analogous to that described in the first paragraph of Example 1, from 0.625 g of 1-[2(R)-[1(R or S)-benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cydobutylpropionyl]pyrrolidine (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (iMix), there was obtained 0.384 g of l-[3-cyclobutyl-2(R)-[l(R or S)- -26- (hydroxycarbamoyl)-2-(3,4&gt;4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-propionyl]morpholine (diastereoisomer 1) in the form of a white solid. nmr (MeOD): 3.77-3.69 (m, 1H); 3.61 (dd, J = 14,6,1H); 3.53-3.44 (m, 2H); 3.39-3.31 (m, 2H); 2.93-2.85 (m, 2H); 2.84 (s, 3H); 2.26-2.13 (m, 1H); 2.07-1.71 (m, 8H); 1.69-1.46 (m, 4H); 1.36 (s, 3H); 1.33 (s, 3H); MS:409 (M+H)+.
Example 21
In a manner analogous to that described in the first paragraph of Example 1, from 0.176 g of 8-[2(R)-[l(R or S)-benzyloxycarbainoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-l,4-dioxa-8-azaspiro[4,5]decane (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), there was obtained 0.084 g of 8-[3-cyclo-butyl-2(RMl(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-l,4-dioxa-8-azaspiro[4,5]decane (diastereoisomer 1) in the form of a white solid. nmr (MeOD): 4.02 (s, 4H); 3.81-3.60 (m, 5H); 3.99 (dd, J = 14,6,1H); 3.20-3.10 (m, 1H); 2.93-2.85 (m, 1H); 2.84 (s, 3H); 2.21-2.09 (m, 1H); 2.06-1.93 (m, 2H); 1.80-1.46 (m, 10H); 1.35 (s, 3H); 1.33 (s, 3H); MS:481 (M+H)+.
Example 22
In a manner analogous to that described in the first paragraph of Example 1, from 0.443 g of 1-[2(R)-[1(R or S&gt;benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cydobutylpropionyl]-4-methoxypiperidine (diastereoisomer 1) there was obtained 0.319 g of l-[3-cydobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-methoxypiperidine (diastereoisomer 1) in the form of a white solid. nmr (MeOD): 3.96-3.80 (m, 2H); 3.69-3.59 (m, 1H); 3.54-3.23 (m, 7H); 3.18-3.09 (m, 1H); 2.93-2.80 (m, 4H); 2.21-2.09 (m, 1H); 2.07-1.41 (m, 12H); 1.41-1.38 (m, 6H); MS:453 (M+H)+.
The starting material was prepared as follows -27- LV 11319 (i) A solution of 0.925 g of 1-[2(R)-[1(R or S)-(tert.butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]-4-hydroxypiperidine in 8 ml of dimethylformamide was treated with 1.08 g of methyl iodide and 1.79 g of silver oxide. The mixture was stirred at room temperature in the dark for 2 days. Additional portions of 0.54 g of methyl iodide and 0.895 g of silver oxide were then added and the mixture was stirred for a further 3 days. The solvent was evaporated and the residue was suspended in ethyl acetate and filtered. The ethyl acetate solution was concentrated and the residue was purified by flash chromatography on silica gel using ethyl acetate for the elution. There was obtained 0.61 g of 1-[2(R)-[1(R or S)-(tert.butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)-ethyl]-3-cyclobutylpropionyl]-4-methoxypiperidine in the form of a colourless gum. (ii) In a manner analogous to that described in Example 1 (viii)-(ix) from 0.61 g of 1-[2(RM1(R or S)-(tert.butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-4-methoxypiperidine there was obtained 0.443 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-4-methoxypiperidine (diastereoisomer 1) in the form of a colourless gum.
Example 23
In a manner analogous to that described in the first paragraph of Example 1, from 0.94 g of l-[2(R&gt;[l(RS)-benzyloxycarbonoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cydobutylpropionyl]-octahydro-azocine (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), there was obtained 0.663 g of l-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]octahydroazocine (diastereoisomer 1) in the form of a white solid: nmr (MeOD): 3.77 (dd, J = 14,10,1H); 3.66-3.43 (m, 4H); 3.33 (dd, J = 14,5,1H); 3.07 (dt, J = 10,4,1H); 2.91-2.81 (m, 4H); 2.29-2.16 (m, 1H); 2.10-1.95 (m, 2H); 1.90-1.46 (m, 16H); 1.34 (s, 6H); MS:451 (M+H)+. -28-
Example 24
In a manner analogous to that described in the first paragraph of Example 1, from 0.37 g of 1-[2(RH1(R or S)-benzyloxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3-oxazolidinyl)ethyl]-3-cyclobutylpropionyl]piperidine (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (v)-(ix) using 3-(bromomethyl)-5,5-dimethyloxazolidine-2,4-dione in place of l-(bromomethyl)-3,4,4-trimethyl-2,5-imidazolinedione, there was obtained 0.131 g of l-[3-cydobutyi-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3-oxazolidinyl)ethyl]propionyl]piperidine (diastereoisomer 1) in the form of a white solid: nmr (MeOD): 3.72-3.53 (m, 5H): 3.39 (dd, J = 14,6,1H), 3.14 (dt, J = 10,4,1H); 2.95-2.86 (m, 1H); 2.23-2.11 (m, 1H); 2.08-1.94 (m, 2H); 1.90-1.44 (m, 18H); MS:410 (M+H)+.
Examr&gt;le 25
In a manner analogous to that described in the first paragraph of Example 1, from 0.42 g of 1-[2(RH1(R or S)-benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]hexahydro-azepine (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), there was obtained 0.197 g of l-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]hexahydroazepine (diastereoisomer 1) in the form of a white solid: nmr (MeOD): 3.77-3.64 (m, 2H); 3.62-3.45 (m, 3H); 3.33 (dd, J = 14,5,1H); 3.07 (dt, J * 10,4,1H); 2.91-2.81 (m, 4H); 2.24-2.13 (m, 1H); 2.09-1.95 (m, 2H); 1.90-1.47 (m, 14H); 1.35 (s, 3H); 1.34 (s, 3H); MS:437 (M+H)+.
Example 26
In a manner analogous to that described in the first paragraph of Example 1, from 0.37 g of 1-[2(R)-[1(R or S)-benzyloxycarbamoyl)-2-(hexahydro-l,3-dioxopyrazolo[l,2-a][l,2,4]triazol-2-yl)ethyl]-3-cyclo-butylpropionyl]piperidine (diastereoisomer 1), prepared in a manner analogous to that described in Example 1 (i)-(ix), using 2-(bromomethyl)-hexahydro-l,3-dioxopyrazolo[l,2-a][l,2,4]triazole, there was obtained 0.118 g -29- LV 11319 of l-[3-cyclobutyl-2(R)-[2-(hexahydro-l,3-dioxopyrazolo[l,2-a][l,2,4]triazol-2-yl)-l(R or SMhydroxycarbamoyl)ethyl]propionyl]piperidine in the form of a white solid. mnr (MeOD): 3.68-3.56 (m,8H); 3.52-3.39 (m,2H); 3.17-3.09 (m,lH); 2.97-2.90 (m,lH); 2.35-2.27 (m,2H); 2.21-2.11 (m,lH); 2.07-1.95 (M,2H); 1.88-1.44 (xn,12H) MS:422 (M+H)+.
Example 27
In a manner analogous to that described in the first paragraph of Example 1, from 0.222 g of 1-[2(R or S)-(benzyloxycarbamoyl)-2-phthal-imidoethyl]-3-cyclobutylpropionyl]piperidine prepared in a manner analogous to that described in Example l(i)-(ix) using N-(bromomethyl)-phthalimide, there was obtained 0.013 g of l[3-cyclobutyl-(2(R)-[l(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]propionyl]piperidine (diastereo-isomer 1) in the form of a white solid. nmr (MeOD): 7.87-7.75 (m.4H); 3.83 (dd,J = 14.8,1H); 3.66-3.58 (m,3H); 3.53-3.45 (m,lH); 3.35-3.25 (m,lH); 3.20-3.12 (m,lH); 3.04-2.97 (m,lH); 2.23-2.11 (m,lH); 2.08-1.95 (m,2H); 1.89-1.41 (m,12H); MS:428 (M+H)+
The following Examples illustrate pharmaceutical preparations containing the hydroxamic acid derivatives provided by the present invention:
Example A
Tablets containing the following ingredients may be produced in a conventional manner:
Ingredient Per tahlet
Hydroxamic acid derivative 10.0 mg
Lactose 125.0 mg
Com starch 75.0 mg
Talc 4.0 mg
Magnesium stearate 1.0 m?
Total weight 215.0 mg -30-
Example B
Capsules containing the following ingredients may be produced in a 5 conventional manner:
Inffredient Per caūsule Hydroxamic acid derivative 10.0 mg Lactose 165.0 mg Com starch 20.0 mg Talc Capsule fill weight 5.0 mg 200.0 mg -31- LV 11319
Cteims 1. Compounds of the general formula R1
wherein
Rl represents cyclopropyl, cyclobutyl, cydopentyl or cyclohexyl; R2 represents a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring which is attached via the N atom and which, when it is monocyclic, optionally contains NR1 2 3, 0, S, SO or SO2 as a ring member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, 0x0, ketalized 0x0, amino, mono(lower alkyl)amino, di(lower alkyl) amino, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyimino; R3 represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO2 as a additional ring member, (c) is substituted by 0x0 on one or both C atoms adjacent to the linking N atom and (d) is optdonally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or 0x0 and/or on any additional N atom(s) by lower alkyl or aryl; R3 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; m stands for 1 or 2; and n stands for 1-4; and pharmaceutically acceptable salts thereof. 1
Compounds according to claim 1, vvherein Rl represents cyclopropyl, cyclobutyl or cyclopentyl; 2 R2 represents a 5-, 6- or 7-membered monocyclic or bridged N-heterocyclic 3 ring which is attached via the N atom and which, when it is monocyclic, -32- optionaUy contains NR4, O, S, SO or SO2 as a ring member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, 0x0, ketalized 0x0, amino, monoQower alkyl)amino&gt; di(lower alkyl) amino, carboxy, lower alkoxycarbonyl, hydroxymethyl, 5 lower alkoxymethyl, carbamoyl, monoflower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyimino; R3 represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionalIy contains N, 0 and/or S as an additional ring member in a position or positions other than adjacent to the linking 10 N atom, (c) is substituted by 0x0 on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or 0x0 and/or on any additional N atom(s) by lower alkyl or aryl; and R4 represents hydrogen, lower alkyl or a protecting group. 15 3. Compounds according to daim 1 or daim 2, wherein R2 represents l-pyrrolidinyl, piperidino, 4-aryl-l-piperazinyl, morpholino, tetrahydro-l,4-thiazin-4-yl, tetrahydro-l,4-thiazin-4-yl l,l-dioxide, thiazolidin-3-yl, hexahydroazepino or octahydroazodno optionally 20 substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, ketalized 0x0 or monoQower alkyl)-carbamoyl; or 3-azabicyclo[3.2.2]nonane. 4. Compounds according to daim 3, wherein R2 represents piperidino or hydroxypiperidino. 25 5. Compounds according to daim 4, wherein hydroxypiperidino is 4-hydroxypiperidino. 6 Compounds according to any one of claims 1 to 5, wherein R3 30 represents a group of the formula
(b) (c) (g) -33- LV 11319 wherein R5 and R6 each represent hydrogen or together represent an additional bond or the remainder of a fused benzene ring; R7 represents hydrogen, lower alkyl or aryl; X represents -CO-, -CH2-, -CHQower alkyl&gt;-, -CGower alkyl)2-, -NH-, -N(lower alkyl)- or -0-; or, when R7 represents lower alkyl and X represents -NGower alkyl)-, the lower alkyl groups can be joined to form a 5-, 6- or 7-membered ring; and R9, RI0 each represent hydrogen or lower alkyl. 7. Compounds according to daim 6, wherein R3 represents a group of formula c), R7 represents lower alkyl and X represents -CGower alkyl)2-. 8. Compounds according to daim 7, wherein R3 represents 3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl. 9. Compounds according to any one of claims 1 to 8, wherein m and n stand for 1. 10. l-[3-Cyclopropyl-2(R)-[lGt or S)-Giydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]piperidine. 11. l-[3-Cydopropyl-2-(R)-[l (R or S)-Giydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-piperidinol. 12. l-[3-Cyclobutyl-2Gt)-[l (R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]piperidine. 13. l-[3-Cyclobutyl-2(R)-[lGt or S&gt;Giydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-piperidinol. 14. l-[3-Cydopentyl-2[Gt)-[l(R or S)-Giydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-piperidinol. 15. l-[3-Cyclopentyl-2(R&gt;[l(R or S)-Giydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl3piperidine. -34- 16. A compound according to daim 2, selected from: 3-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl3propionyl]-3-azabicyclo[3.2.2]nonane, 3-[3-cydopropyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-3-azabicydo[3.2.2]nonane and 3- [3-cydopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-[3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-3-azabicydo[3.2.2]nonane. 17. A compound according to daim 1, selected from: l-[3-cydohexyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]piperidine, 4- [3-cydopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]tetrahydro-l&gt;4-thiazine, 4-[3-cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]tetrahydro-l,4-thiazine S,S-diozide, 4-[3-cyclobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4)4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]tetrahydro-l,4-thiazine, 4-[3-cyclohexyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4»4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]tetrahydro-l,4-thiazine, 3- [3-cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-5,5-dimethyl-N-propyl-4(R)-thiazolidinecarboxamide, 4- [3-cydopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]morpholine, 3- [3-cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2&gt;5-dioxo-l-imidazolidinyl)ethyl]propionyl]-N,5&gt;5-trimethyl-4(R)-thiazolidinecarboxamide, 4- [3-cyclobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl3-4-phenylpiperazine, 4-[3-cyclobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]morpholine, l-[3-cyclobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3I4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]pyTrolidine, 8-[3-cyclobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-l,4-dioxa-8-azaspiro[4,5]decane, -35- LV 11319 l-[3-cydobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]-4-methoxypiperidine&gt; l-[3-cydobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]octahydroazocine, 5 l-[3-cyclobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(5,5-dimethyl-2,4- dioxo-3-oxazolidinyl)ethyl]propionyl]piperidine, l-[3-cydobutyl-2(R)-[l(R or SMhydroxycarbamoyl)-2-(3,4,4-trimethyl- 2.5- dioxo-l-imidazolidinyl)ethyl]propionyl]hexahydroazepine, l-[3-cydobutyl-2(RH2-(hexahydro-l,3-dioxopyrazolo[l,2-a][l,2,4]triazol-1D 2-yl)-l(R or S)-(hydroxycarbamoyl)ethyl]propionyl]piperidine and l-[3-cydobutyl-2(R)-[l(R or S)-(hydroxycabamoyl)-2-phthalimido-ethyl]propionyl]piperidine. 18. Compounds of the general formula 15 R1
R3 wherein R1, R2, R3, m and n have the significance given in daim 1. 20 19. Compounds of the general formula R1
(IV) wherein R1, R2, R3, m and n have the significance given in claim 1. 25 -36- 20. Compounds according to any one of claims 1-17 for use as therapeutically active substances, especially in the control or prevention of degenerative joint diseases or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis. 21. A process for the manufacture of the compounds claimed in any one of claims 1-17, which process comprises (a) reacting an acid of the general formula R1
wherein R1, R2, R3, m and n have the significance given in claim 1, with a compound of the general formula h2n-oz m wherein Z represents hydrogen, triGower alkyl)silyl or diphenyl(lower alkyl)silyl, and, where required, cleaving off any diphenylQower alkyl)silyl group present in the reaction product, or (b) catalytically hydrogenating a compound of the general formula -37- LV 11319 R1
wherein R1, R2, R3, m and n have the significance given in claim 1 and Bz represents benzyl, and, if desired, converting a compound of formula I obtained into a pharmaceutically acceptable salt. 22. A process for the manufacture of medicaments, especially for use in the control or prevention of degenerative joint diseases or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis, which process comprises bringing a compound according to any one of claims 1-17 with a therapeutically inert carrier material and bringing the mixture into a galenical administration form. 23. A medicament containing a compound according to any one of claims 1-17 and a therapeutically inert carrier material. 24. A medicament for the control or prevention of degenerative joint diseases or for the treatment of invasive tumours, atherosclerosis or multiple sclerosis, containing a compound according to any one of claims 1-17 and a therapeutically inert carrier material. 25. The use of a compound according to any one of claims 1-17 in the control or prevention of illnesses, especially for the control or prevention of degenerative joint diseases or for the treatment of invasive tumours, atherosclerosis or multiple sclerosis. -39- LV 11319
Abstract
The invention provides hydroxamic acid derivatives of the general formula
R3 (0 wherein R1 represents cyclopropyl, cydobutyl, cyclopentyl or cyclohexyl; R2 represents a saturated 5- to 8-membered monocydic or bridged N-heterocyclic ring which is attached via the N atom and which, when it is monocyclic, optionally contains NR4, 0, S, SO or SO2 as a ring member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, 0x0, ketalized 0x0, amino, mono(lower alkyl)amino, di(lower alkyl)amino,carboxy, lower alkoxycarbonyl, hydroxy-methyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyimino; R3 represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, 0 and/or S, SO or SO2 as an additional ring member, (c) is substituted by 0x0 on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or 0x0 and/or on any additional N atom(s) by lower alkyl or aryl; R4 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; m stands for 1 or 2 and n stands for 1-4, and pharmaceutically acceptable salts thereof, which are collagenase inhibitors useful in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis. They can be manufactured either by hydroxamidating a corresponding novel carboxylic acid or by deprotecting a corresponding novel benzyloxycarbamoyl compound.

Claims (25)

LV 11319 Patentformulas punkti 1. Savienojumi ar kopējo formulu (I) HO R1 '&quot;MJ HClaims 1. Compounds of the general formula (I) HO R1 '&quot; MJ H ω kurā: R1 ir ciklopropilgrupa, ciklobutilgrupa, ciklopentilgrupa vai cikloheksilgrupa; R2 ir piesātināts 5 - 8 locekļu monociklisks vai tiltiņu saturošs slāpekļa heterocikls, kas piesaistīts ar slāpekļa atomu, un kurš, ja tas ir monociklisks, neobligāti satur kā cikla locekli NR4,0, S, SO vai S02 un/vai neobligāti aizvietots pie viena vai vairākiem oglekļa atomiem ar hidroksilgrupu, zemāko alkilgrupu, zemāko alkoksigrupu, oksogrupu, ketalizētu oksogrupu, aminogrupu, ar zemāko alkilgrupu monoaizvietotu aminogrupu, ar zemākām alkilgrupām divaizvietotu aminogrupu, karboksil-grupu, zemāko alkoksikarbonilgrupu, oksimetilgrupu, zemāko alkoksimetil-grupu, karbamoilgrupu, ar zemāko alkilgrupu monoaizvietotu karbamoilgrupu, ar zemākām alkilgrupām divaizvietotu karbamoilgrupu vai hidroksiiminogrupu; R3 ir 5 vai 6 locekļu slāpekļa heterocikls,kas: (a) ir piesaistīts ar slāpekļa atomu, (b) neobligāti satur kā papildus cikla locekli N, 0 un/vai S, SO, S02, (c) ir aizvietots ar oksogrupu pie viena vai abiem oglekļa atomiem blakus saistošajam slāpekļa atomam, 1 (d) neobligāti kondensēts ar benzola gredzenu vai neobligāti aizvietots pie viena vai vairākiem citiem oglekļa atomiem ar zemāko alkilgrupu vai okso-grupu un/vai neobligāti aizvietots pie slāpekļa atoma(iem) ar zemāko alkilgrupu vai arilgrupu; R4 ir ūdeņraža atoms, zemākā alkilgrupa, arilgrupa, aralkilgrupa vai aizsarggrupa; m ir 1 vai 2; un n ir 1 - 4; kā arī to farmaceitiski pieņemamās sālis.wherein: R1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R2 is a saturated 5- to 8-membered monocyclic or bridge-containing nitrogen heterocycle linked to a nitrogen atom and, if monocyclic, optionally contains as a member of the ring NR4.0, S, SO or SO2 and / or optionally substituted on one or more of the nitrogen atoms; multiple carbon atoms with hydroxyl, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, lower alkyl mono-substituted amino, lower alkyl double substituted amino, carboxyl, lower alkoxycarbonyl, oxymethyl, lower alkoxymethyl, carbamoyl, lower alkyl mono-substituted carbamoyl, lower alkyl substituted with carbamoyl or hydroxyiminogroup; R3 is a 5 or 6 membered nitrogen heterocycle which: (a) is attached to a nitrogen atom, (b) optionally contains as an additional ring member N, O and / or S, SO, SO2, (c) is substituted with an oxo group at one or both carbon atoms adjacent to the bonding nitrogen atom, 1 (d) optionally condensed with a benzene ring or optionally substituted with one or more other carbon atoms having the lowest alkyl or oxo and / or optionally substituted with the nitrogen atom (s) with the lower alkyl or aryl; R4 is hydrogen, lower alkyl, aryl, aralkyl or protecting group; m is 1 or 2; and n is 1 to 4; as well as their pharmaceutically acceptable salts. 2. Savienojumi pēc punkta 1, kuros: R1 ir ciklopropilgrupa, ciklobutilgrupa vai ciklopentilgrupa; R2 ir 5, 5 vai 7 locekļu monociklisks vai tiltiņu saturošs slāpekļa heterocikls, kas piesaistīts ar slāpekļa atomu, un kurš, ja tas ir monociklisks, neobligāti satur kā cikla locekli NR4 , O, S, SO vai S02 un/vai neobligāti aizvietots pie viena vai vairākiem oglekļa atomiem ar hidroksilgrupu, zemāko alkilgrupu, zemāko alkoksigrupu, oksogrupu, ketalizētu oksogrupu, aminogrupu, ar zemāko alkilgrupu monoaizvietotu aminogrupu, ar zemākām alkilgrupām divaizvietotu aminogrupu, karboksilgrupu, zemāko alkoksikarbo-nilgrupu, oksimetilgrupu, zemāko alkoksimetilgrupu, karbamoilgrupu, ar zemāko alkilgrupu monoaizvietotu karbamoilgrupu, ar zemākām alkilgrupām divaizvietotu karbamoilgrupu vai hidroksiiminogrupu; R3 ir 5 vai 6 locekļu slāpekļa heterocikls,kas: (a) ir piesaistīts ar slāpekļa atomu, (b) neobligāti satur kā papildus cikla locekli N, 0 un/vai S, (c) ir aizvietots ar oksogrupu pie viena vai abiem oglekļa atomiem blakus saistošajam slāpekļa atomam, (d) neobligāti kondensēts ar benzola gredzenu vai neobligāti aizvietots pie viena vai vairākiem citiem oglekļa atomiem ar zemāko alkilgrupu vai oksogrupu un/vai neobligāti aizvietots pie slāpekļa atoma(iem) ar zemāko alkilgrupu vai arilgrupu; R4 ir ūdeņraža atoms, zemākā alkilgrupa, vai aizsarggrupa.Compounds according to claim 1, wherein: R 1 is cyclopropyl, cyclobutyl or cyclopentyl; R2 is a 5, 5 or 7 membered monocyclic or bridge-containing nitrogen heterocycle linked to a nitrogen atom and, if monocyclic, optionally contains as ring member NR4, O, S, SO or SO2 and / or optionally substituted on one or multiple carbon atoms with hydroxyl, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, lower alkyl mono-substituted amino, lower alkyl with two substituted amino, carboxyl, lower alkoxycarbonyl, oxymethyl, lower alkoxymethyl, carbamoyl, lower alkyl mono-substituted carbamoyl, lower alkyl substituted with carbamoyl or hydroxyiminogroup; R3 is a 5 or 6 membered nitrogen heterocycle which: (a) is attached to a nitrogen atom, (b) optionally contains as an additional ring member N, O and / or S, (c) is substituted by an oxo group at one or both carbon atoms (d) optionally condensed with a benzene ring or optionally substituted with one or more other carbon atoms having the lowest alkyl or oxo group and / or optionally substituted on the nitrogen atom (s) with the lower alkyl or aryl; R4 is hydrogen, lower alkyl, or protecting group. 3. Savienojumi pēc punkta 1 vai 2, kuros R2 ir 1-pirolidinilgrupa, piperidinogrupa, 4-aril-1-piperazinilgrupa, morfolinogrupa, tetrahidro-1,4-tiazin-4-ilgrupa, tetrahidro-1,4-tiazin-4-il-1,1 -dioksīdgrupa, tiazolidin-3-ilgrupa, heksahidroazepinogrupa vai oktahidroazocinogrupa, kas neobligāti aizvietotas pie viena vai vairākiem oglekļa atomiem ar hidroksilgrupu, zemāko alkilgrupu, zemāko alkoksigrupu, ketalizētu oksigrupu vai ar zemāko alkilgrupu monoaizvietotu karbamoilgrupu; vai arī R2 ir 3-azabiciklo[3.2.2]-nonilgrupa.Compounds according to claim 1 or 2, wherein R 2 is 1-pyrrolidinyl, piperidinogroup, 4-aryl-1-piperazinyl, morpholinogroup, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl il-1,1-dioxide, thiazolidin-3-yl, hexahydroazepinogroup or octahydroazocinogroup optionally substituted on one or more carbon atoms with hydroxyl, lower alkyl, lower alkoxy, ketalized oxo or lower alkyl mono-substituted carbamoyl; or R2 is 3-azabicyclo [3.2.2] -nonyl. 4. Savienojumi pēc punkta 3, kuros R2 ir piperidinogrupa vai hidroksipiperidinogrupa.Compounds according to claim 3, wherein R 2 is piperidinogroup or hydroxypiperidinogroup. 5. Savienojumi pēc punkta 4, kuros hidroksipiperidinogrupa ir 4-hidroksipiperidinogrupa. 2 LV 11319Compounds according to claim 4, wherein the hydroxypiperidinogroup is a 4-hydroxypiperidinogroup. 2 LV 11319 6. Savienojumi pēc jebkura no punktiem 1 - 5, kuros R3 ir grupa ar formuluCompounds according to any one of claims 1 to 5, wherein R 3 is a group of formula R5 un R6 katrs atsevišķi ir ūdeņraža atoms, vai abi kopā veido papildus saiti ar pārējo kondensētā benzola gredzena daļu; R7 ir ūdeņraža atoms, zemākā alkiigrupa vai arilgrupa; X ir -CO-, -CH2-, -CH(zemākā alkiigrupa)-, -C(zemākā alkilgrupa)2-, -NH-, -N(zemākā alkiigrupa)- vai -0-; vai ari, kad R7 ir zemākā alkiigrupa un X ir -N(zemākā alkiigrupa)-, zemākās alkilgrupas var būt savienotas un veidot 5, 6 vai 7 locekļu ciklu; un R9, R10 katrs atsevišķi ir ūdeņraža atoms vai zemākā alkiigrupa.R5 and R6 are each independently hydrogen, or both together form an additional bond to the rest of the fused benzene ring; R7 is hydrogen, lower alkyl or aryl; X is -CO-, -CH 2 -, -CH (lower alkyl) -, -C (lower alkyl) 2-, -NH-, -N (lower alkyl) - or -O-; or when R7 is lower alkyl and X is -N (lower alkyl) - lower alkyl may be bonded to form a 5, 6 or 7 membered ring; and R9, R10 are each independently hydrogen or lower alkyl. 7. Savienojumi pēc punkta 6, kuros R3 ir grupa ar formulu c), bet R7 ir zemākā alkiigrupa un X ir -C(zemākā alkilgrupa)2-.Compounds according to claim 6, wherein R 3 is a group of formula c), and R 7 is lower alkyl and X is -C (lower alkyl) 2-. 8. Savienojumi pēc punkta 7, kuros R3 ir 3,4,4-trimetil-2,5-diokso-1-imidazolidinilgrupa.Compounds according to claim 7, wherein R 3 is 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl. 9. Savienojumi pēc jebkura no punktiem 1 - 8, kuros m un n ir 1.Compounds according to any one of claims 1 to 8, wherein m and n are 1. 10. 1-{3-Ciklopropil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}piperidīns.10. 1- {3-Cyclopropyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl } piperidine. 11. 1-{3-Ciklopropil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}-4-piperidinols.11. 1- {3-Cyclopropyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl } -4-piperidinol. 12.1- {3-Ciklobutil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}piperidīns.12.1- {3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} piperidine . 13.1- {3-Ciklobutil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propioni!}-4-piperidinols.13.1- {3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl}} -4-piperidinol. 14.1- {3-Ciklopentil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}-4-piperidinols.14.1- {3-Cyclopentyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} - 4-piperidinol. 15.1- {3-Ciklopentil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}-4-piperidīns. 315.1- {3-Cyclopentyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} 4-piperidine. 3 16. Savienojums pēc punkta 2, kas ņemts no grupas: 3-{3-Ciklobutil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}-3-azabiciklo[3.2.2]nonāns, 3-{3-ciklopropil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}-3-azabiciklo[3.2.2]nonāns, 3- {3-ciklopentil-2(R)-(1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etii]propionil}-3-azabiciklo[3.2.2]nonāns.A compound according to claim 2, taken from the group: 3- {3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5) dioxo-1-imidazolidinyl) ethyl] propionyl} -3-azabicyclo [3.2.2] nonane, 3- {3-cyclopropyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3) 4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} -3-azabicyclo [3.2.2] nonane, 3- {3-cyclopentyl-2 (R) - (1 (R or S) ) - (Hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} -3-azabicyclo [3.2.2] nonane. 17. Savienojums pēc punkta 1, kas ņemts no grupas: 1{3-cikloheksil-2(R)-[1(R vai S)-(hidroksikarbamoil)- 2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]prbpionil}piperidīns, 4- {3-ciklopentil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetii-2,5-diokso-1-imidazolidinil)etil]propionil}tetrahidro- 1.4- tiazins, 4-{3-ciklopentol-2(R)-[1 (R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2I5-diokso-1-imidazolidinil)etil]propionil}tetrahidro- 1.4- tiazīn-S,S-dioksīds, 4-{3-ciklobutil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}tetrahidro- 1.4- tiazīns, 4-{3-cikloheksil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}tetrahidro- 1.4- tiazīns, 3- {3-ciklopentil-2(R)-[1 (R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}-5,5-dimetil-N-propii-4(R)-tiazolidīnkarboksamīds, 4- {3-ciklopentil-2(R)-[1 (R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinii)etil]propionil}morfolīns, 3- {3-ciklopentil-2(R)-[1 (R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}-N,5,5-trimetil-4(R)-tiazolidīnkarboksamīds, 4- {3-ciklobutil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinii)etil]propionil}-4-fenilpiperazīns, 4-{3-ciklobutil-2(R)-[1 (R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}morfolīns, 1-{3-ciklobutil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}pirolidīns, 8-{3-ciklobutil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}-1,4-dioksa-8-azaspiro[4,5]dekāns, 1-{3-cikloheksil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolidinil)etil]propionil}-4-metoksipiperidīns, 1-{3-ciklobutil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetii-2,5-diokso-1-imidazolidinil)etil]propionil}oktahidroazocins, 4 LV 11319 1-{3-ciklobutil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(5,5-dimetil-214-diokso-3-oksazolidinil)etil]propionil}piperidīns, 1-{3-ciklobutil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1-imidazolinil)etil]propionil}heksahidroazepīns, 1 -{3-ciklobutil-2(R)-[2-(heksahidro-1,3-dioksapirazolo-[1,2-a][1,2,4]triazol-2-il)-1 (R vai S)-(hidroksikarbamoil)etil]propionil}piperidīns, 1-{3-ciklobutil-2(R)-[1(R vai S)-(hidroksikarbamoil)-2-ftalimidoetil]propionil}piperidīns.17. A compound according to claim 1, taken from the group: 1- {3-cyclohexyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5- dioxo-1-imidazolidinyl) ethyl] prbionyl} piperidine, 4- {3-cyclopentyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5) dioxo-1-imidazolidinyl) ethyl] propionyl} tetrahydro-1,4-thiazine, 4- {3-cyclopentol-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4- trimethyl-2'-5-dioxo-1-imidazolidinyl) ethyl] propionyl} tetrahydro-1,4-thiazine-S, S-dioxide, 4- {3-cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) - 2- (3,4,4-Trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} tetrahydro-1,4-thiazine, 4- {3-cyclohexyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} tetrahydro-1,4-thiazine, 3- {3-cyclopentyl-2 (R) - [1] (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} -5,5-dimethyl-N-propyl-4 (R) thiazolidinecarboxamide, 4- {3-cyclopentyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2 - (3,4,4-Trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} morpholine, 3- {3-cyclopentyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) - 2- (3,4,4-Trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} -N, 5,5-trimethyl-4 (R) -thiazolidinecarboxamide, 4- {3-cyclobutyl-2 ( R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} -4-phenylpiperazine, 4- {3- cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} morpholine, 1- {3 -cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} pyrrolidine, 8- { 3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl} -1.4 dioxa-8-azaspiro [4,5] decane, 1- {3-cyclohexyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2, 5-dioxo-1-imidazolidinyl) ethyl] propionyl} -4-methoxypiperidine, 1- {3-cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4- trimethyl-2,5-dioxo 1-imidazolidinyl) ethyl] propionyl} octahydroazocin, 4H-11319 1- {3-cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (5,5-dimethyl-214-dioxo) 3-oxazolidinyl) ethyl] propionyl} piperidine, 1- {3-cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo) -1-imidazolinyl) ethyl] propionyl} hexahydroazepine, 1- {3-cyclobutyl-2 (R) - [2- (hexahydro-1,3-dioxapyrazolo [1,2-a] [1,2,4] triazole) -2-yl) -1 (R or S) - (hydroxycarbamoyl) ethyl] propionyl} piperidine, 1- {3-cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] propionyl} piperidine. 18. Savienojumi ar kopējo formulu (II)18. Compounds of the general formula (II) R3 kurā R1, R2, R3, m un π nozīmes atbilst punkta 1 minētajām.R3 wherein R1, R2, R3, m and π are as defined in claim 1. 19. Savienojumi ar kopējo formulu (IV) R1Compounds of the general formula (IV) R 1 (IV) kurā R1, R2, R3, m un n nozīmes atbilst punktā 1 minētajām.(IV) wherein R1, R2, R3, m and n are as defined in claim 1. 20. Savienojumi pēc jebkura no punktiem 1-17 pielietojumam par terapeitiski aktīvām vielām, sevišķi deģeratīvu locītavu slimību ārstēšanai un profilaksei vai ļaundabīgo audzēju, aterosklerozes un multiplās sklerozes ārstēšanai. 5Compounds according to any one of claims 1-17 for use as therapeutically active substances, in particular for the treatment and prophylaxis of degenerative joint diseases or for the treatment of malignant tumors, atherosclerosis and multiple sclerosis. 5 21. Paņēmiens savienojumu pēc jebkura no punktiem 1-17 iegūšanai, kas paredz: (a) skābes ar kopējo formulu (II)A process for the preparation of compounds according to any one of claims 1 to 17, comprising: (a) acids of the general formula (II) R3 (Π) kura R1, R2, R3, m un n nozīmes atbilst punkta 1 minētajam, iedarbību ar savienojumu ar kopējo formulu (III) (III) H2N-OZ kurā Z ir ūdeņraža atoms, tri(zemākā alkilgrupa)sililgrupa vai difenil(zemākā alkilgrupa)sililgrupa, un, ja nepieciešams, reakcijas produktā esošās difenil(zemākā alkilgrupa)sililgrupas nošķelšanu; vai (b) savienojuma ar kopējo formulu (IV) R1 BzO.R3 (Π) with the meanings of R1, R2, R3, m and n, as defined in claim 1, with the compound of formula (III) (III) H2N-OZ wherein Z is hydrogen, tri (lower alkyl) silyl or diphenyl (\ t lower alkyl) silyl and, if necessary, diphenyl (lower alkyl) silyl group in the reaction product; or (b) R1bzO of the compound of formula (IV). R2 (TV) kurā R1, R2, R3, m un n nozīmes atbilst punktā 1 minētajām, un Bz ir benzilgrupa, katalītisku hidrogenēšanu, un, ja nepieciešams, tādā veidā iegūtā savienojuma ar formulu (I) pārvēršanu farmaceitiski pieņemamā sālī.R 2 (TV) wherein R 1, R 2, R 3, m and n are as defined in claim 1, and B 2 is benzyl, catalytic hydrogenation, and, if necessary, conversion of the compound of formula (I) thus obtained into a pharmaceutically acceptable salt. 22. Paņēmiens zāļu ražošanai, sevišķi tādu, kas paredzētas deģeneratīvu locītavu slimību ārstēšanai vai profilaksei vai ļaundabīgo audzēju, aterosklerozes un multiplās sklerozes ārstēšanai, kas ietver 6 LV 11319 savienojuma pēc jebkura no punktiem 1-17 apvienošanu ar terapeitiski inertu nesēja vieiu un šī maisījuma izveidošanu gatavā zāļu formā.A method for the manufacture of a medicament, in particular for the treatment or prophylaxis of degenerative joint diseases or for the treatment of malignant tumors, atherosclerosis and multiple sclerosis, comprising combining a compound of any of claims 1-17 with a therapeutically inert carrier compound and forming a mixture thereof. in the final dosage form. 23. Ārstniecības līdzeklis, kas sastāv no savienojuma pēc jebkura no punktiem 1 -17 un terapeitiski inertas nesēja vielas.A medicament comprising a compound according to any one of claims 1 to 17 and a therapeutically inert carrier. 24. Ārstniecības līdzeklis, kas paredzēts deģeneratīvu locītavu slimību ārstēšanai un profilaksei vai ļaundabīgo audzēju, aterosklerozes un multiplās sklerozes ārstēšanai, satāv no savienojuma pēc jebkura no punktiem 1 -17 un terapeitiski inertas nesēja vielas.A therapeutic agent for the treatment and prevention of degenerative joint diseases or for the treatment of malignant tumors, atherosclerosis and multiple sclerosis, is comprised of a compound of any one of claims 1 to 17 and a therapeutically inert carrier. 25. Savienojumu pēc jebkura no punktiem 1-17 pielietojums tādu ārstniecības līdzekļu ražošanai, kas paredzēti deģeneratīvu locītavu slimību ārstēšanai vai profilaksei vai ļaundabīgo audzēju, aterosklerozes un multiplās sklerozes ārstēšanai. 7Use of compounds according to any one of claims 1-17 for the manufacture of a medicament for the treatment or prevention of degenerative joint diseases or for the treatment of malignant tumors, atherosclerosis and multiple sclerosis. 7
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